EA026628B1 - Противовирусные соединения против rsv - Google Patents
Противовирусные соединения против rsv Download PDFInfo
- Publication number
- EA026628B1 EA026628B1 EA201590748A EA201590748A EA026628B1 EA 026628 B1 EA026628 B1 EA 026628B1 EA 201590748 A EA201590748 A EA 201590748A EA 201590748 A EA201590748 A EA 201590748A EA 026628 B1 EA026628 B1 EA 026628B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- chloro
- alkyl
- mmol
- group
- methyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 206
- 230000000840 anti-viral effect Effects 0.000 title description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 230000010076 replication Effects 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 61
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 51
- 229910052736 halogen Inorganic materials 0.000 claims description 44
- 150000002367 halogens Chemical class 0.000 claims description 44
- 239000000460 chlorine Substances 0.000 claims description 35
- 239000001257 hydrogen Substances 0.000 claims description 29
- 125000001072 heteroaryl group Chemical group 0.000 claims description 28
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- 239000013256 coordination polymer Substances 0.000 claims description 22
- 229920006395 saturated elastomer Polymers 0.000 claims description 21
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 208000015181 infectious disease Diseases 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 150000002431 hydrogen Chemical class 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
- 239000003937 drug carrier Substances 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 241000725643 Respiratory syncytial virus Species 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 125000002619 bicyclic group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000002950 monocyclic group Chemical group 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 46
- 239000012453 solvate Substances 0.000 abstract description 7
- 239000003112 inhibitor Substances 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 3
- 238000002560 therapeutic procedure Methods 0.000 abstract description 2
- -1 5-substituted benzimidazole Chemical class 0.000 description 190
- 238000005481 NMR spectroscopy Methods 0.000 description 139
- 239000000203 mixture Substances 0.000 description 121
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 115
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 111
- 230000015572 biosynthetic process Effects 0.000 description 100
- 239000000543 intermediate Substances 0.000 description 97
- 238000003786 synthesis reaction Methods 0.000 description 95
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
- 239000000243 solution Substances 0.000 description 73
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 56
- 239000002904 solvent Substances 0.000 description 55
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 52
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 47
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- 238000005160 1H NMR spectroscopy Methods 0.000 description 37
- 239000011541 reaction mixture Substances 0.000 description 34
- 239000007787 solid Substances 0.000 description 31
- 239000012044 organic layer Substances 0.000 description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
- 239000000047 product Substances 0.000 description 29
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 25
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
- 239000002585 base Chemical class 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000002253 acid Substances 0.000 description 21
- 239000012267 brine Substances 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 17
- 239000012634 fragment Substances 0.000 description 16
- 230000014509 gene expression Effects 0.000 description 16
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 14
- 239000003054 catalyst Substances 0.000 description 14
- 239000003480 eluent Substances 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 14
- 238000010898 silica gel chromatography Methods 0.000 description 14
- 229910000104 sodium hydride Inorganic materials 0.000 description 14
- 229910000024 caesium carbonate Inorganic materials 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- 125000003003 spiro group Chemical group 0.000 description 13
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 12
- 125000004429 atom Chemical group 0.000 description 12
- 150000004820 halides Chemical class 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 12
- 230000002285 radioactive effect Effects 0.000 description 12
- 239000012312 sodium hydride Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 11
- 239000000843 powder Substances 0.000 description 11
- 241000700605 Viruses Species 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 150000001298 alcohols Chemical class 0.000 description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 150000007942 carboxylates Chemical class 0.000 description 8
- 150000004985 diamines Chemical class 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 8
- SXOVJOBXZPCKRA-UHFFFAOYSA-N spiro[1h-indole-3,4'-piperidine]-2-one Chemical compound O=C1NC2=CC=CC=C2C11CCNCC1 SXOVJOBXZPCKRA-UHFFFAOYSA-N 0.000 description 8
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 8
- 230000009385 viral infection Effects 0.000 description 8
- FOZVXADQAHVUSV-UHFFFAOYSA-N 1-bromo-2-(2-bromoethoxy)ethane Chemical compound BrCCOCCBr FOZVXADQAHVUSV-UHFFFAOYSA-N 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 208000036142 Viral infection Diseases 0.000 description 7
- 150000007513 acids Chemical class 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 7
- 239000005457 ice water Substances 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- 125000004076 pyridyl group Chemical group 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 230000005526 G1 to G0 transition Effects 0.000 description 5
- 229910052805 deuterium Inorganic materials 0.000 description 5
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 5
- 239000012280 lithium aluminium hydride Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- HWYHDWGGACRVEH-UHFFFAOYSA-N n-methyl-n-(4-pyrrolidin-1-ylbut-2-ynyl)acetamide Chemical compound CC(=O)N(C)CC#CCN1CCCC1 HWYHDWGGACRVEH-UHFFFAOYSA-N 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 238000006751 Mitsunobu reaction Methods 0.000 description 4
- OGXXBQMYLYGKFN-UHFFFAOYSA-N [5-chloro-1-(3-methylsulfonylpropyl)indol-2-yl]methanol Chemical compound ClC1=CC=C2N(CCCS(=O)(=O)C)C(CO)=CC2=C1 OGXXBQMYLYGKFN-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 125000003226 pyrazolyl group Chemical group 0.000 description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- GAZQOVJZPPYPDV-UHFFFAOYSA-N spiro[1h-pyrrolo[2,3-c]pyridine-3,4'-piperidine]-2-one Chemical compound O=C1NC2=CN=CC=C2C11CCNCC1 GAZQOVJZPPYPDV-UHFFFAOYSA-N 0.000 description 4
- VCWXWCKINURMLB-UHFFFAOYSA-N spiro[1h-pyrrolo[2,3-c]pyridine-3,4'-thiane]-2-one Chemical compound O=C1NC2=CN=CC=C2C11CCSCC1 VCWXWCKINURMLB-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- XYSKIRJLAHQPQT-UHFFFAOYSA-N tert-butyl 2-oxospiro[1h-pyrrolo[2,3-c]pyridine-3,4'-piperidine]-1'-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC21C1=CC=NC=C1NC2=O XYSKIRJLAHQPQT-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- JUXIFXMIXNKBJY-UHFFFAOYSA-N 1'-benzylspiro[1h-pyrrolo[2,3-c]pyridine-3,4'-piperidine]-2-one Chemical compound O=C1NC2=CN=CC=C2C1(CC1)CCN1CC1=CC=CC=C1 JUXIFXMIXNKBJY-UHFFFAOYSA-N 0.000 description 3
- HUCXRCCJHDFVCI-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-c]pyridin-2-one Chemical compound C1=NC=C2NC(=O)CC2=C1 HUCXRCCJHDFVCI-UHFFFAOYSA-N 0.000 description 3
- KFSMQSHAWYERIP-UHFFFAOYSA-N 1,3-dihydropyrrolo[3,2-c]pyridin-2-one;hydrobromide Chemical compound Br.N1=CC=C2NC(=O)CC2=C1 KFSMQSHAWYERIP-UHFFFAOYSA-N 0.000 description 3
- IEEXAHWWHZVZQI-UHFFFAOYSA-N 1-[[5-chloro-1-(3-methylsulfonylpropyl)benzimidazol-2-yl]methyl]spiro[2H-indole-3,3'-azetidine] Chemical compound ClC1=CC2=C(N(C(=N2)CN2CC3(CNC3)C3=CC=CC=C23)CCCS(=O)(=O)C)C=C1 IEEXAHWWHZVZQI-UHFFFAOYSA-N 0.000 description 3
- YUYZEKDRDBWNGG-UHFFFAOYSA-N 1-bromo-2-(1-bromopropan-2-yloxy)propane Chemical compound BrCC(C)OC(C)CBr YUYZEKDRDBWNGG-UHFFFAOYSA-N 0.000 description 3
- YYWACUFAVLSCPF-UHFFFAOYSA-N 1-bromo-2-(2-bromoethylsulfanyl)ethane Chemical compound BrCCSCCBr YYWACUFAVLSCPF-UHFFFAOYSA-N 0.000 description 3
- VJABSSGXEWXCLY-UHFFFAOYSA-N 3-methylsulfonylpropylazanium;chloride Chemical compound Cl.CS(=O)(=O)CCCN VJABSSGXEWXCLY-UHFFFAOYSA-N 0.000 description 3
- CZUGFKJYCPYHHV-UHFFFAOYSA-N 3-methylthiopropanol Chemical compound CSCCCO CZUGFKJYCPYHHV-UHFFFAOYSA-N 0.000 description 3
- ZJSKQQAHJZBYOL-UHFFFAOYSA-N 4-[5-chloro-2-(hydroxymethyl)indol-1-yl]butanenitrile Chemical compound ClC1=CC=C2N(CCCC#N)C(CO)=CC2=C1 ZJSKQQAHJZBYOL-UHFFFAOYSA-N 0.000 description 3
- PVNNVHUZZREEOS-UHFFFAOYSA-N 5-chloro-1-(3-cyanopropyl)indole-2-carboxylic acid Chemical compound ClC1=CC=C2N(CCCC#N)C(C(=O)O)=CC2=C1 PVNNVHUZZREEOS-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- MJOYJCJBSMLVBX-UHFFFAOYSA-N ClC1=CC2=C(N(C(=N2)CN2C(C3(CNC3)C3=CC=CC=C23)=O)CCCS(=O)(=O)C)C=C1 Chemical compound ClC1=CC2=C(N(C(=N2)CN2C(C3(CNC3)C3=CC=CC=C23)=O)CCCS(=O)(=O)C)C=C1 MJOYJCJBSMLVBX-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- WTPFGNCJZHVQBG-UHFFFAOYSA-N N1C(C#N)=NC=C2N=CC=C21 Chemical class N1C(C#N)=NC=C2N=CC=C21 WTPFGNCJZHVQBG-UHFFFAOYSA-N 0.000 description 3
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- JIYBHWLFTWVDIG-UHFFFAOYSA-N [5-chloro-1-(4-fluorobutyl)pyrrolo[3,2-b]pyridin-2-yl]methanol Chemical compound ClC1=CC=C2N(CCCCF)C(CO)=CC2=N1 JIYBHWLFTWVDIG-UHFFFAOYSA-N 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 125000005907 alkyl ester group Chemical group 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
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- YODZTKMDCQEPHD-UHFFFAOYSA-N thiodiglycol Chemical compound OCCSCCO YODZTKMDCQEPHD-UHFFFAOYSA-N 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
- C07F9/65068—Five-membered rings having the nitrogen atoms in positions 1 and 3 condensed with carbocyclic rings or carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/20—Spiro-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/20—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/20—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Epidemiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP12188694 | 2012-10-16 | ||
| EP13159431 | 2013-03-15 | ||
| PCT/EP2013/071525 WO2014060411A1 (en) | 2012-10-16 | 2013-10-15 | Rsv antiviral compounds |
Publications (2)
| Publication Number | Publication Date |
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| EA201590748A1 EA201590748A1 (ru) | 2015-07-30 |
| EA026628B1 true EA026628B1 (ru) | 2017-04-28 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EA201590748A EA026628B1 (ru) | 2012-10-16 | 2013-10-15 | Противовирусные соединения против rsv |
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| EP (1) | EP2909195B1 (ko) |
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| BR (1) | BR112015008325B1 (ko) |
| CA (1) | CA2884491C (ko) |
| CL (1) | CL2015000925A1 (ko) |
| CY (1) | CY1119566T1 (ko) |
| DK (1) | DK2909195T3 (ko) |
| EA (1) | EA026628B1 (ko) |
| EC (1) | ECSP15014941A (ko) |
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| HK (1) | HK1210462A1 (ko) |
| HR (1) | HRP20171351T1 (ko) |
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| TWI515187B (zh) | 2010-12-16 | 2016-01-01 | 健生科學愛爾蘭無限公司 | 作為呼吸道融合病毒抗病毒劑之吲哚類 |
| TWI501967B (zh) * | 2010-12-16 | 2015-10-01 | Janssen R&D Ireland | 作為呼吸道融合病毒抗病毒劑之氮雜吲哚類 |
| TWI527814B (zh) | 2010-12-16 | 2016-04-01 | 健生科學愛爾蘭無限公司 | 作為呼吸道融合病毒抗病毒劑之氮雜苯并咪唑類 |
| HUE060743T2 (hu) | 2012-04-26 | 2023-04-28 | Bristol Myers Squibb Co | Gyógyszerészeti kompozíciók, amelyek tartalmaznak imidazothiadiazol- és imidazopiridazinszármazékokat mint proteáz aktívált receptor 4 (PAR4) inhibitorokat trombocitaaggregációk kezelésére |
| TWI568722B (zh) | 2012-06-15 | 2017-02-01 | 葛蘭馬克製藥公司 | 作爲ｍＰＧＥＳ－１抑制劑之三唑酮化合物 |
| KR102092612B1 (ko) | 2012-06-15 | 2020-03-25 | 얀센 사이언시즈 아일랜드 언리미티드 컴퍼니 | 호흡기 합포체 바이러스의 항바이러스제로서의 헤테로사이클로 치환된 1,3-디하이드로-2h-벤즈이미다졸-2-온 유도체 |
| JP6437452B2 (ja) | 2013-01-14 | 2018-12-12 | インサイト・ホールディングス・コーポレイションＩｎｃｙｔｅ Ｈｏｌｄｉｎｇｓ Ｃｏｒｐｏｒａｔｉｏｎ | Ｐｉｍキナーゼ阻害剤として有用な二環式芳香族カルボキサミド化合物 |
| KR102403306B1 (ko) | 2013-01-15 | 2022-06-02 | 인사이트 홀딩스 코포레이션 | Pim 키나제 저해제로서 유용한 티아졸카복스아마이드 및 피리딘카복스아마이드 화합물 |
| EP2997028A1 (en) * | 2013-05-14 | 2016-03-23 | F.Hoffmann-La Roche Ag | Aza-oxo-indoles for the treatment and prophylaxis of respiratory syncytial virus infection |
| CN105392787B (zh) * | 2013-05-14 | 2017-11-24 | 豪夫迈·罗氏有限公司 | 用于治疗和预防呼吸道合胞病毒感染的氮杂‑氧代‑吲哚 |
| BR112016002638A2 (pt) * | 2013-08-12 | 2017-08-01 | Hoffmann La Roche | novos aza-oxo-indóis para o tratamento e profilaxia de infecção pelo virus sincicial respiratório |
| CA2914541A1 (en) * | 2013-08-15 | 2015-02-19 | F. Hoffmann-La Roche Ag | Novel aza-oxo-indoles for the treatment and prophylaxis of respiratory syncytial virus infection |
| JP2016528298A (ja) | 2013-08-23 | 2016-09-15 | インサイト・コーポレイションＩｎｃｙｔｅ Ｃｏｒｐｏｒａｔｉｏｎ | Ｐｉｍキナーゼ阻害剤として有用なフロピリジン及びチエノピリジンカルボキシアミド化合物 |
| US9850251B2 (en) | 2013-12-10 | 2017-12-26 | Shandong Danhong Pharmaceutical Co., Ltd. | Imidazole derivative used as antiviral agent and use therof in preparation of medicament |
| TWI671299B (zh) | 2014-04-14 | 2019-09-11 | 愛爾蘭商健生科學愛爾蘭無限公司 | 作為ｒｓｖ抗病毒化合物之螺脲化合物 |
| US9580418B2 (en) | 2014-07-14 | 2017-02-28 | Incyte Corporation | Bicyclic aromatic carboxamide compounds useful as Pim kinase inhibitors |
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| GB201417707D0 (en) | 2014-10-07 | 2014-11-19 | Viral Ltd | Pharmaceutical compounds |
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| EP3305790B1 (en) | 2015-06-08 | 2020-08-05 | Shangdong Danhong Pharmaceutical Co., Ltd. | Method for preparing imidazole derivative and intermediate thereof and crystal form |
| HUE060259T2 (hu) | 2015-07-22 | 2023-02-28 | Enanta Pharm Inc | Benzodiazepin származékok mint RSV-gátlók |
| TWI734699B (zh) | 2015-09-09 | 2021-08-01 | 美商英塞特公司 | Ｐｉｍ激酶抑制劑之鹽 |
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| HUE053078T2 (hu) * | 2016-01-20 | 2021-06-28 | Janssen Sciences Ireland Unlimited Co | Aril-szubsztituált pirimidinek influenza vírus fertõzésben való alkalmazásra |
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| CN109369658B (zh) * | 2017-08-08 | 2020-01-31 | 沈阳药科大学 | 一种螺[吡咯烷-3,3`-氧化吲哚]环系的合成方法 |
| BR112020006334A2 (pt) | 2017-09-29 | 2020-09-24 | Enanta Pharmaceuticals, Inc. | combinação de agentes farmacêuticos como inibidores de rsv |
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| WO2022184606A1 (en) * | 2021-03-01 | 2022-09-09 | Janssen Sciences Ireland Unlimited Company | Synthesis of rilematovir |
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